1. Field of the Invention
This invention relates to novel colchicine derivatives that are useful for treating various types of cancer.
2. Background of the Invention
Colchicine is a known compound having the following formula 
The rings are referred to as A (the phenyl ring showing methoxygroups at 1, 2, and 3), B (7-membered ring with the amide group at 7), and C (the third ring). The compound has been used to treat gout and also exhibits antitumor activity.
The antitumor activity of colchicine, which is the major alkaloid of the autumn crocus, Colchicum autumnale, and the African climbing lily, Gloriosa superba, was first reported at the beginning of the 20th century. The elucidation of its structure was finally completed from X-ray studies and a number of total syntheses (see Shiau et al. J. Pharm. Sci. 1978, 67(3) 394-397). Colchicine is thought to be a mitotic poison, particularly in tyhmic, intestinal, and hermatopoietic cells, which acts as a spindle poison and blocks the kinesis. Its effect on the mitotic spindle is thought to represent a special case of its effects on various organized, labile, fibrillar systems concerned with structure and movement.
Thiocolchicine is a compound of the above formula, wherein the 10-methoxy group is replaced by a 10-methylthio group. The removal of the acetyl group from the 7-position results in N-deacetylcolchicine or N-deactylthiocolchicine. We have now discovered new derivatives of colchicine and thiocolchicine that exhibit useful anticancer activity.
One aspect of this invention is a compound represented by the formula 
wherein
R is C(O)xe2x80x94(CHR4)mxe2x80x94Axe2x80x94R1 where
m is 1-10,
A is S, O, N or a covalent bond,
R1 is substituted phenyl or substituted benzoyl;
B is methoxy or methylthio;
R2 is methoxy, hydroxy, or methylenedioxy when taken together with R3;
R3 is methoxy, hydroxy, a monosaccharide radical, or is methylenedioxy when taken together with R2; and
R4 is H or is H or methyl when m is 1.
Another aspect of this invention is a compound represented by the formula 
wherein
R is C(O)xe2x80x94(CHR4)mxe2x80x94Axe2x80x94R1 where
m is 0-10;
A is oxygen, sulfur, nitrogen, or a covalent bond;
R1 is phenyl substituted with one to five substituents (the substituents being selected from halo, lower alkyl, cyano, nitro, amino, halogenated lower alkyl, carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted 5 or 6 membered heterocyclic ring, an imide ring, lower alkoxycarbonyl, and lower alkylcarbonylamino, optionally substituted cycloalkyl of 3-7 carbons, optionally substituted naphtyl, an optionally substituted imide ring, an optionally substituted 5 or 6 member heterocycle (with at least one N, S, or O in the ring), or an optionally substituted fused heterocyclic or fused carboxyclic ring system;
B is methoxy or methylthio;
R2 is methoxy, hydroxy, or methylenedioxy when taken together with R3;
R3 is methoxy, hydroxy, a monosaccharide radical, or is methylenedioxy when taken together with R2; and
R4 is H or H or methyl when m is 1.
Another aspect of this invention is a compound represented by the formula 
wherein
B is methoxy or methylthio;
R2 is methoxy, hydroxy, or methylenedioxy when taken together with R3;
R3 is methoxy, hydroxy, a monosaccharide radical, or is methylenedioxy when taken together with R2; and
X is a linking group.
Another aspect of the invention is a pharmaceutical composition useful for treating cancer in a warm-blooded animal, which composition comprises compound of the invention as defined herein in combination with a pharmaceutically acceptable excipient.
Another aspect of this invention is a method for treating cancer in a warm-blooded animal, which method comprises administering a therapeutically effective amount of a compound of the invention as defined herein. The compound is administered in a therapeutically effective dose by appropriate administration, e.g. orally, topically, or parenterally.
Other aspects of this invention will be apparent to one of skill in the art by reviewing the ensuing specification.